The present invention relates to novel amide compounds and salts thereof. More particularly, it relates to novel amide compounds and salts thereof which have pharmacological activities such as 5-hydroxytryptarine (5-HT) antagonism and the like.
Said amide compounds and their salts are useful as a 5HT antagonist for treating or preventing central nervous system (CNS) disorders such as anxiety, depression, obsessive compulsive disorders, migraine,.anorexia, Alzheimer""s disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse (e.g., with cocaine, ethanol, nicotine and benzodiazepines), schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus in human being and animals.
With regard to the state of the art in this field, for example, the following amide compounds are disclosed in Japanese Patent Kokai No. Hei 11(1999)-130750. 
wherein R1 is quinolyl, quinazolinyl, isoquinolyl or pyridyl group, R3 is phenyl, cyclo(lower)alkyl, indolyl, lower alkyl-indazolyl or 2,3-dihydroindolyl group, Y is single bond, lower alkylene or lower alkenylene group, and A is lower alkylene group.
As a result of an extensive study, the inventors of the present invention found some amide compounds which have strong pharmacological activities.
The amide compounds of the present invention are novel and can be represented by the formula (I): 
wherein
R1 is an N-containing heterocyclic group selected from an imidazolyl, a triazolyl, a pyridyl, a pyridazinyl, a pyrimidinyl and a pyrazinyl group, each of which may be substituted with one or more lower alkyl groups,
R2 is a hydrogen atom or a lower alkyl group, and
R3 is a phenyl group substituted with thienyl or halophenyl; a thienyl group substituted with thienyl, phenyl or halophenyl; a pyrrolyl group substituted with phenyl; a thiazolyl group substituted with phenyl; an indolyl group substituted with lower alkyl and/or halo(lower)alkyl; a fluorenyl group; or a carbazolyl group, provided that
(1) the imidazolyl group for R1 is substituted with one or more alkyl groups, when R3 is a phenyl group substituted thienyl; an indolyl group substituted with lower alkyl; or carbazolyl group,
(2) the imidazolyl group for R1 is substituted with two lower alkyl groups, when R3 is a phenyl group substituted with halophenyl, or
(3) R1 is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, a 4-(lower alkyl)-imidazol-1-yl or a 4,5-di(power alkyl)-imidazol-1-yl group, when R3 is fluorenyl group.
Suitable salts of the compounds (I) are conventional non-toxic pharmaceutically acceptable salts and may include salts with inorganic bases, for example, alkali metals (e.g. sodium or potassium), alkaline earth metals (e.g. calcium or magnesium) or ammonia; salts with organic bases, for example, organic amines (e.g. triethylamine, pyridine, picoline, ethanolamine, triethanolamine, dicyclohexylamine or N,Nxe2x80x2-dibenzylethylenediamine); inorganic acid addition salts (e.g. hydrochloride, hydrobromide, hydriodide, sulfate or phosphate); organic carboxylic or sulfonic acid addition salts (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate or p-toluenesulfonate); salts with basic or acidic amino acids (e.g. arginine, aspartate or glutamate); and the like, and preferable examples thereof are the inorganic or organic acid addition salts.
According to the present invention, the object compounds (I) can be prepared by the following process: 
wherein R1, R2 and R3 are each as defined above.
In the above and subsequent descriptions of the present. specification, suitable examples and illustrations of the various definitions which the present invention include within the scope are explained in detail in the following.
The term xe2x80x9clowerxe2x80x9d is intended to mean 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise indicated.
Suitable lower alkyl groups and lower alkyl moieties in the halo(lower)alkyl groups may include straight or branched ones, having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl and hexyl, and preferably the ones having 1 to 4 carbon atom(s), among which the most preferred one is methyl.
Suitable halo(lower)alkyl groups may include lower alkyl groups substituted with one or more halogen atoms such as fluoromethyl, fluoroethyl, fluoropropyl, trifluoromethyl, chloromethyl, dichloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, iodomethyl, iodoethyl, iodopropyl, and the like.
Suitable halophenyl groups may include fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, trichlorophenyl, bromophenyl, dibromophenyl, tribromophenyl, iodophenyl, and the like.
When imidazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl groups for R1 is substituted with two or more lower alkyl groups, said lower alkyl groups may be the same or different from each other.
And also, when indolyl group for R3 is substituted with two or more lower alkyl groups and/or two or more halo(lower)alkyl groups, said lower alkyl groups and halo(lower)alkyl groups may be the same or different from each other.
The process for preparing the object compounds (I) is explained in detail in the following.
The object compound (I) and its salt can be prepared by reacting a compound (II) or its reactive derivative at the amino group or a salt thereof with a compound (III) or its reactive derivative at the carboxy group or a salt thereof.
Suitable reactive derivatives at the amino group of the compound (II) may include Schiff""s base type imine or its tautomeric enamine type isomer formed by the reaction of the compound (II) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide, bis(trimethylsilyl)urea or the like; a derivative formed by the reaction of a compound (II) with phosphorus trichloride or phosgene, and the like.
Suitable salts of the compound (II) and its reactive derivative can be referred to those as exemplified for the compound(l).
Suitable reactive derivatives at the carboxy group of the compound (III) may include the acid halides, acid anhydrides, activated amides, activated esters and the like.
Suitable examples of such reactive derivatives may be the acid chloride; the acid azide; the mixed acid anhydride with an acid such as substituted phosphoric acid [e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid or halogenated phosphoric acid], dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g. methanesulfonic acid], aliphatic carboxylic acid [e.g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid] or aromatic carboxylic acid [e.g. benzoic acid]; symmetrical acid anhydride; activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or activated ester [e.g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH3)2N*=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester or 8-quinolyl thioester], or ester with an N-hydroxy compound [e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinide, N-hydroxyphthaimide or 1-hydroxy-1H-benzotriazole], and the like.
The reactive derivative can optionally be selected from the above according to the kind of the compound (III) to be used.
Suitable salts of the compound (III) and its reactive derivative may be the base salts such as alkali metal salts [e.g. sodium salt or potassium salt], alkaline earth metal salts [e.g. calcium salt or magnesium salt], ammonium salts, organic base salts [e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt or N,Nxe2x80x2-dibenzylethylenediamine salt], or the like, and acid addition salts as exemplified for the compound (I).
The reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol or ethanol], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction, or a mixture thereof.
In this reaction, when the compound (III) is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,Nxe2x80x2-dicyclohexylcarbodiimide; N-cyclohexyl-Nxe2x80x2-morpholinoethylcarbodiimide; N-cyclohexyl-Nxe2x80x2-(4-diethylaminocyclohexyl)carbodiimide; N-Nxe2x80x2-diethylcarbodiiide, N,Nxe2x80x2-diisopropylcarbodiimide; N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl) carbodiimide; N,Nxe2x80x2-carbonylbis-(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylixine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; triallyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; diphenyl phosphorylazide; thionyl chloride; oxalyl chloride; lower alkyl haloformate [e.g. ethyl chloroformate, isopropyl chloroformate, etc.]; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)-isoxazolium hydroxide intramolecular salt; benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride or the like.
The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower) alkylmorpholine, N,N-di(lower)alkylbenzylamine or the like,
The reaction is usually carried out under cooling to warming, although the reaction temperature is not critical.
The object compound (I) of the present invention can be isolated and purified in a conventional manner, for example extraction, precipitation, fractional crystallization, recrystallization, chromatography and the like.
The object compound (I) thus obtained can be converted to its corresponding salt by the conventional method.
The object compound (I) and salts thereof may include solvates [e.g., enclosure compound (e.g., hydrate, etc.)].
Among the starting compounds (II) and (III), novel compounds can be prepared by the method described in the following Examples or similar method thereto.
In order to exhibit the usefulness of the present invention, the activities of the compounds (I) are shown in the following.
Test Method.
[3H]-mesulergine Binding
The affinity of the test drugs for the 5-HT2c binding site can be determined by assessing their ability to displace [3H]-mesulergine in the rat prefrontal cortex. The method employed was similar to that of Pazos et al, 1984.
The membrane suspension (500 xcexcl) was incubated with [3H]-mesulergine (1 nM) in Tris HCl buffer containing CaCl24 mM and ascorbic acid 0.1 % (pH 7.4) at 37xc2x0 C. for 30 minutes. Non-specific binding was measured in the presence of mianserin (1 xcexcM). 30 nM spiperone was used to prevent binding to 5-HT2A sites. Test drugs (10xe2x88x926 M) were added in a volume of 100 xcexcl. The total assay volume was 1000 xcexcl. Incubation was stopped by rapid filtration using a Brandel cell harvester and radioactivity measured by scintillation counting.
The IC50 values were determined using a four parameter logistic program (DeLean 1978) and the phi (the negative logarithm of the inhibition constant) calculated from the Cheng Prusoff equation where:       Ki    =                  IC        50                    1        +                  C          ⁢                      /                    ⁢          Kd                                                                                            Ki                =                                  inhibition  constant                                                                                                        C                =                                                      concentration  of                                      ⁢                                                            [                                                              3                                                        ⁢                                      H                                    ⁢                                      ]                                    ⁢                                      -mesulergine                                                                                                                    Kd          =                                    affinity  of  mesulergine  for                          ⁢            5            ⁢                                          -HT                                            2                ⁢                c                                      ⁢                            binding  site.                                          
Test Compounds:
(1) N-(1-Methyl-1H-indol-5-yl)-Nxe2x80x2-(3-pyridyl)urea (reference compound)
(2) N-(3-(yridin-3-yl)phenyl)-9H-fluorene-1-carboxamide (Example 1)
(3) N-(3-(pyrimidin-5-yl)phenyl)-9H-fluorene-1-carboxamide (Example 2)
(4) N-(3-(pyridazin-4-yl)phenyl)-9H-fluorene-1-carboxamide (Example 6)
Test Result:
As shown in above, the object compounds (I) of the present invention exhibit pharmacological activities such as 5-HT antagonism, especially, 5-HT2cantagonism, and therefore are useful as 5-HT antagonist for treating or preventing central nervous system (CNS) disorders such as anxiety, depression, obsessive compulsive disorders, migraine, anorexia, Alzheimer""s disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse (e.g., with cocaine, ethanol, nicotine and benzodia pines), schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus, and the like.
For therapeutic or preventive administration, the object compounds (I) of the present invention are used in a form of conventional pharmaceutical preparation which contains said compound as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration. The pharmaceutical preparations may be in a solid form such as tablet, granule, powder or capsule, or in a liquid form such as solution, suspension, syrup, emulsion or lemonade.
If needed, there may be included in the above preparations auxliary substances, stabilizing agents, wetting agents and other commonly used additives such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol and the like.
While the dosage of the compound (I) may vary from and also depend upon the age, conditions of the patient, kind of diseases or conditions, kind of the compound (I) to be applied, etc., in general, 0.01-500 mg of the compound (I) may be administered to a patient per day.
An average single dose of about 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 20 mg, 50 mg, 100 mg of the compound (I) may be used in treating the diseases.
The following Examples are given for illustrating the present invention, but it is to be noted that the scope of the present invention is not limited by these Examples.
The following Examples are given only for the purpose of illustrating the present invention in more detail.